PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related deaths and the third most commonly diagnosed cancer in the United States. Despite the advantages of polyp screening for early detection, treatment options for advanced CRC rely on aggressive chemotherapy. Therefore, targeted therapy for the treatment of CRC is critically needed. Strikingly, clinical evidence has shown that compared to normal intestinal tissue, human colorectal tumors exhibit a down-regulation of gene expression of all components of the circadian clock molecular machinery. The circadian clock is the endogenous biological pacemaker which controls several physiological, endocrine and metabolic processes that operate to maintain organismal homeostasis within a strict 24- hour period. Several lines of evidence suggest that disruption of circadian rhythms results in cancer, yet the precise molecular mechanisms and detailed signaling pathways have yet to be elucidated. Moreover, the crosstalk between the circadian clock and proliferative pathways in the intestine is not fully elucidated, and more specifically, how this crosstalk is involved in CRC initiation and progression in vivo remains unresolved. To address this knowledge gap, we have generated a novel genetically engineered mouse model (GEMM) to elucidate the effects of circadian clock disruption on intestinal cell proliferation and CRC. We propose that genetic disruption of the molecular clock machinery aberrantly drives Wnt/b-Catenin signaling in the intestine. One goal of this proposal is to delineate the role of the circadian clock on Wnt- dependent proliferation pathways in the intestine, including pathways that govern cancer-initiating cell populations. A second goal of this proposal is to define the molecular mechanism of how the circadian clock impinges on Wnt/b-Catenin dependent transcriptional and epigenetic pathways. Our studies have important clinical implications in understanding how disruption of the biological pacemaker, on the molecular level, alters tumor initiation and disease progression to CRC. These findings provide novel insight into the potential for therapeutic targeting of the circadian clock for treatment of CRC, in addition to other tumors types dependent on activated Wnt signaling.